Process for ethinylating 17-ketosteroids

ABSTRACT

Process for preparing 17 Alpha -ethinyl-17 Beta -hydroxysteroids characterized by the partial formula   WHEREIN R1 is lower alkyl by ethinylating 17-ketosteroids characterized by the partial formula   WHEREIN R1 has the same meaning as above, with acetylene in the presence of an alkali alcoholate of a tertiary alcohol and in the presence of a solvent in the absence of any tertiary alcohol.

United States Patent 1 1 Wieske et al.

[ 1 Sept. 18, 1973 PROCESS FOR ETHINYLATING l7-KETOSTEROIDS Inventors:Reinhold Wieske; Paul-Eberhard Schulze, both of Berlin, GermanyAssignee: Sekering Alrtiengesellschaft,

Berlin/Bergkamen, Germany Filed: June 3, 1971 Appl. No.: 149,808

Foreign Application Priority Data June 13, 1970 Germany P 20 30 056.5

US. Cl... 260/3974, 260/2395, 260/239.S5 R,

260/239.55 C, 260/3975, 260/3975 A Int. Cl. C07c 167/20 Field of Search260/3974, 397.5

References Cited OTHER PUBLICATIONS J. Amer. Chem. Soc., 78, (1956),article by Reingold et al., pages 2477-2479, relied on.

Primary Examiner-Elbert L. Roberts AttorneyMichael S. Striker [57]ABSTRACT Process for preparing 17a-ethinyl-l7B-hydroxysteroidscharacterized by the partial formula wherein R is lower alkyl byethinylating l7- ketosteroids characterized by the partial formula 6Claims, No Drawings PROCESS FOR ETHINYLATING 17-KETOSTEROIDS Thisinvention relates to a process for ethinylating l7-ketosteroids. Moreparticularly the invention relates to a process for preparingl7a-ethinyl-l7flhydroxysteroids characterized by the partial formulawherein R, is lower alkyl, by ethinylating a 17- ketosteroidcharacterized by the partial formula o It:

in which R, has the same meaning as above with acetylene in the presenceof an alkali alcoholate of a tertiary alcohol and of a solvent but inthe absence of a tertiary alcohol.

The definition of R, as lower alkyl in the above formulae is intended todesignate alkyl containing one to six carbon atoms. The alkyl groups canbe straight or branched chain, saturated or unsaturated. Illustrativeexamples of lower alkyl R, include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl,tertiary pe'nty'l, hexyl and the corresponding unsaturated analogs.Preferably R, designates methyl, ethyl or propyl.

lnstances of suitable starting'materials for use in the process of theinvention are the l7-ketosteroids of the estrane and androstane serieswhich can be substituted in the conventional manner, for instance byfree, esterified or etherified hydroxyl groups in any of the 1-, 3-, 6-or 1 1- positions; free or functional oxo groups in any of the 3- or 1l-positions;methyl groups in any of the 1-,

.2- or 6- positions; or methylene groups in any of the 1,2-, 5,10- or6,7- positions. Furthermore, the 17- ketosteroids can contain anaromatic A- or 8- ring. or a double bond, for example, in any of the 1-,2-, 4-, 5(6)-, 5(10)-, 8(9)-, 8( l4)- or 9(1 1 positions. It is ofcourse to be understood that the starting compounds can have a multiplenumber of the aforenamed substituents and/or double bonds.

The ethinylation of l7-ketosteroids with acetylene in the presence ofalcoholates of tertiary alcohols and of tertiary alcohols is known (DBP1,013,649; DBP 1,016,707; DAS 1,264,441 and Ringold et al.-J.Amer.-

Chem.Soc., 78, 1956, 2477-2479).

In accordance with the known procedure, the 17- ketosteroid isdissolved-in a suitable solvent reacted with a solution of alkalialcoholate in an excess of the tertiary alcohol and acetylene thenconducted into the reaction mixture. The known ethinylation process hasthe disadvantage that in the ethinylation of 17- ketosteroids whose 13-position angular methyl group is alkyl substituted only very smallyields of the desired 17a-ethinyl-l7B-hydroxy-steroid are obtained(H.Smith et al. Chem.Soc. (London), 1964, 4472-4492, especially 4475).Accordingly, the process is suitable only for the synthesis ofl7a-ethinyl-l7B- hydroxysteroidsJhe 13- position angular methyl group ofwhich is unsubstituted.* (*Since this procedure is easily to be carriedout, it is preferably adopted for the large scale manufacture of thesesteroids, although, for obtaining satisfactory yields, reaction times inaccess of 15 hours are necessary.)

It is an object of this invention to provide an ethinylation processthat is not only suitable for preparing 17aethinyl-l7B-hydroxysteroidscontaining an unsubstituted l3 position methyl group but which isequally suitable for effecting the synthesis of l7a-ethinyl-l7B-hydroxysteroids containing an alkyl substituted 13- position methylgroup.

Another object is to provide such a process which is technically lessexpensive to effect than the known ethinylation method.

Still another object of the invention is such a process equallyapplicable to the synthesis of steroid compounds having an unsubstituted13- position methyl group as well as to the synthesis of thecorresponding substituted compounds.

- These and other objects and advantages of the invention will beapparent from a consideration of the following disclosure.

In accordance with the invention, it has now been found that the aboveobjects are attained if the ethinylation of l7-ketosteroids is carriedout with acetylene in the presence of an alkali alcoholate of a tertiaryalcohol and of a solvent but in the absence of any tertiary alcohol.

As alkali alcoholates for use in the process of the invention, there aresuitable alcoholates of tertiary alcohols which have been usedheretofore in the known ethinylation reaction, particularly suitable aresodium or the potassium alcoholates such as for instance sodium orpotassium tertiary butylate and sodium or potassium tertiary amylate.

, As solvent there may be used for the ethinylation process of theinvention any of the solvents conventionally used in ethinylatingreactions. Examples of such solvents include for instance, aromatichydrocarbons such as benzene, toluene or xylene, ethers such asdiethylether, gylcoldimethylether, dioxan or tetrahydrofuran and polaraprotonic solvent such as dimethylformamide, N-methylacetamide ordimethylsulfoxide.

The process of the invention is preferably carried out at a reactiontemperature of less than 60C and most preferably at a temperature offrom +20 to -20C.

The process of the invention can be carried out at normal pressure andalso at elevated pressure and preferably using pressures of up to 5atmospheres.

The working up of the reaction mixture is carried out using theconventional working techniques, for instance by concentration of themixtures in vacuum or through precipitation of the reaction productswith water or dilute mineral acids. As part of the working up, there canbe split off if required from the reaction products, previously presentketal groups, enol groups or enamine groups, if necessary underadditional isomerization of existing double bonds. The recovered crudeproducts can be purified in the conventional manner for instance throughchromatography and/or crystallization.

The following table shows the superiority of the process of theinvention as compared to the known ethinylation method. The reactioninvolved in the compari- TABLE 1 Percent transformation of 3-meth0xy-l8-methyl-2,5( l)-estradiene-l7-one with different tertiary butanolcontents in the reaction mixture Reaction time (hrs.) ml tertiaryButanol 0 ml 11 ml 1 82.3% 31.0% 2 93.3% 37.8% 3 98.8% 4 48.2% 5 49.3%

As this table shows in the reaction of 17-ketosteroids having an alkylsubstituted l3-methyl group, a considerable reaction acceleration andalso a significant increase in yield is realized if the reaction iscarried out in the absence of any tertiary alcohol. In the conversion of17-ketosteroids having an unsubstituted l3-methyl group, the reactionvelocity is increased even further, i.e., a more than 5-fold increase isobserved when the ethinylation is carried out in the absence of thetertiary alcohol.

'TABLE 2 Percent transformation of 3-methoxy-2,5( l0)-estradiene-l7-onewith different tertiary butanol contents in the reaction mixture.Reaction conditions: g steroid, 11 g potassium tertiary butylate in 1 10ml solvent (a) tetrahydrofuran (b) tetrahydrofuran tertiary butanol;procedure analogous to Table l.

ml-tertiary butanol eaction times (hrs.) 0 ml 35 ml 0.5 91.0 1 96.3 36.31.5 98.0 8 98.0 76.5 16 95.1

There are prepared using the process of the invention, pharmacologicallyactive l7a-ethinyl-17B- hydroxysteroids for instance gestation activesteroids, i.e., fertility regulating steroids such as 17a-ethinyl-19-nor-testosterone or 17-a-ethinyl-18-methyl-19-nortestosterone orestrogenic activ steroids such as 3- methoxyl 8-methyl-l7a-ethinyl-l 3,5 (10)-estratrien- 1713-0] and 3-methoxy-l7a-ethinyl-l,3,5(l0)-estratrien-l7B-ol (mestranol). The latter aromatic compounds alsocould be intermediate products for preparing ofl7a-ethinyl-19-nor-testosterone by methods known in the art. Further theproducts prepared by the process of the invention are valuableintermediate products for use in the synthesis of pharmacologicallyactive pregnane derivatives such as l7a-hydroxy-progesteronecaproate,hydrocortisone or prednisolone because it is possible to convert thel7a-ethinyl-side chain in the progesterone or hydrocortine side chain aspredescribed, e.g., by Ruczicka, Helv. chem. Act. 22 (1939) 416,Miescher, Helv. chem. Act. 22 (1939) and 33 (1950) 1840, lnhoffen, Ber.71 (1938) 1032, Hershberg, J. Am. Soc. 73 (1951) 5074, Schoppee, Helv.chem. Act. 26 (1943) l004.

Instances of suitable starting compounds for use in the process of theinvention are the 17-ketosteroids which can be converted intol7a-ethinyl-l7B-hydroxysteroids which are per se pharmacologicallyactive or which constitute important intermediate products for use inthe synthesis of pregnane derivatives. Preferred examples of startingcompounds for the process of the invention are l7-ketosteroids havingthe formula:

wherein R, is lower alkyl and A is one of the groups and in which R ishydroxy, lower alkoxy or lower acyloxy, R is hydrogen or lower alkyl,preferably methyl, X is hydrogen, lower alkoxy, lower acyloxy,morpholino, piperidino or pyrrolidino, Y can be hydrogen or the both Ystogether a free or protected keto group and Z is either 2 hydrogen atomsor a keto group.

In accordance with a further aspect of the invention there are madepossible in accordance with the invention new pharmacologicallyavailable compounds not heretofore available includingl8-methyl-l7a-ethinyl S-androstene-3B-l7B-diol and 3B-hydroxy-l8-methyl- 5-androstene-l7-one.

The following Examples are given in order to more fully illustrate theinvention and are in nowise to be construed as in any way limiting thescope thereof.

EXAMPLE 1 Acetylene was introduced under stirring and over an hourperiod into a mixture cooled to C consisting of 11g potassium tertiarybutylate and 200 ml tetrahydrofuran. 20g Racemic3-methoxy-l8-methyl-2,5(10)- estradiene-l7-one were then introduced intothe mixture and under stirring and at -10C further acetylene introducedtherein over a 3-hour period. After the reaction had ended, the reactionmixture was decomposed by addition thereto of 100 ml methanol and 18.5ml concentrated hydrochloric acid, the solvent distilled off in vacuumat 45-55C and replaced during the distillation with 320 ml water. Themixture was then stirred under ice cooling, the separated productsuctioned off, washed with water until neutral, dried in vacuum andcrystallized out of acetone.

There were thusly recovered 17.6 g l7B-hydroxy-l8-methyl-17a-ethinyl-4-estrene-3-one (85 percent of theory) having amelting point of 207-209C.

EXAMPLE 2 [a1],, 24.1 (Chloroform; c=1 percent) EXAMPLE 3 Acetylene wasintroduced for one hour at -C into a suspension consisting of 5.3gpotassium tertiary butylate in 110 ml tetrahydrofuran. 10g 3-methoxy-l8-ethyl-2,5(10)-estradiene-l7-one were then introduced and furtheracetylene conducted into the resulting mixture for 3 hours. The reactionmixture was worked up as described in Example 1. The crude product wascrystallized out of cyclohexane-diisopropylether and yielded 8.35gl7B-hydroxy-l8-ethyl-l7a-ethinyl-4- estrene-3-one (80.5 percent oftheory) having a melting point of l82-184C. 1

.-26.3 (Chloroform).

EXAMPLE 4 Acetylene was introduced at -5 C for 1 hour into a suspensionconsisting of 5.5 g potassium tertiary butylate in 100 mltetrahydrofuran. 10 g 3-Methoxy-l8- methy1-1,3,5(10)-estratriene-l7-onewere then added and further acetylene introduced at 5C for an additional3 hours, the reaction mixture decomposed by addition thereto of 27 mlpercent sulfuric acid and 14 ml water, and the tetrahydrofuran distilledoff in vacuum and replaced by water. The material which thereuponseparated out was extracted with methylene chloride, themethylenechloride phase washed until neutral and evaporated to dryness.The residue was crystallized out of methylenechloride and yielded 8.41 g3- methoxy-l 8-methyl-17a-ethinyl-l ,3,5( l0)-estratriene- 173-01 (77percent of theory) having a melting point of 98 99C.

[a L, -17.8 (Chloroform).

EXAMPLE 5 Under the reaction conditions described in Example 4, 10 gracemic 3-methoxy-l8-ethyl-l,3,5(10)- estratriene-l7-one wereethinylated. After working up the reaction mixture asdescribed inExample 4 and crystallizing the crude product out of ethylacetate, therewere recovered 8.24 g3-methoxy-18-ethyl-l7aethinyl-1,3,5(l0)-estratriene-l7B-ol (76 percentof theory) having a melting point of 128 130C.

EXAMPLE 6 Acetylene was conducted for 1 hour at 10C into a suspension of6.0 g potassium tertiary butylate in 100 ml tetrahydrofuran and then 10g S-methoxyl,3,5(l0)-estratriene-l7-one were introduced. Thereafterthere was conducted into the mixture under stirring for a further 2hours additional acetylene at l0C. The reaction mixture was furtherworked up as described in Example 4 and the resultant crude productcrystallized out of ethylacetate. There were recovered 9.68 g3-methoxy-i7a-ethinyl-l,3,5(l0)-estratriene- 173-01 (89 percent oftheory) having a melting point of 151 152.5C.

EXAMPLE 7 20 g -3-Hydroxy-1,3,5(10)-estratriene-l7-one were introducedinto a suspension of 25.2 g potassium ter' tiary butylate in 400 mltetrahydrofuran into which acetylene had been introduced for 1 hour at15C. Further acetylene was then conducted into this mixture understirring for an additional 3 hours at 15C and the reaction mixtureworked up as set out in Example 4. The crude product was crystallizedout of acetone and there were recovered 18.7 g .17a-ethinyl-l,3,5( 10)-estratriene-3,l7fl-diol percent of theory)'having a melting point ofl82.5 183.5C.

[ a 1,, +2.6 (Dioxan).

EXAMPLE 8 5 g 4-Estrene-3,17-dione were introduced into a suspension of5.5 g potassium tertiary butylate and 55 m1 tetrahydrofuran into whichacetylene had previously been introduced for 1 hour at 10C. There wasthen introduced into the resulting mixture for another 2 hours, understirring at -10C, additional acetylene, the reaction mixture worked upas described in Example 4 and the crude product crystallized out ofmethylene chloride. There were thusly obtained 4.4 g 173-hydroxy-l7a-ethinyl-4-estrene-3-one (80.4 percent of theory) having amelting point of 205 206C.

1 a 10 -23.8 (Chloroform).

EXAMPLE 9 0 g 18-Methyl-4-estrene-3,17-dione we ethinylated analogouslyto Example 8 in the presence of 11 g potassium tertiary butylate in 1 10ml tetrahydroturan by introducing acetylene for 2 hours at -10C. Afterworking up the reaction mixture as described in Example 4 andcrystallizing the crude product out of methylenechloride there wererecovered 8.28 g 17B-hydroxy-18-methyl-7a-ethinyl-4-estrene- 3-one (76percent of theory) having a melting point of 235 237C.

[ a 1 -32.8 (Chloroform).

EXAMPLE 10 5 g BB-Hydroxy-S-androstene-l7-one were introduced into asuspension of 2.75 g potassium tertiary butylate in 5 ml tetrahydrofuraninto which acetylene has previously been introduced for 1 hour understirring at 15C. Additional acetylene was then introduced into themixture for a further 2 hours at 15C. The reaction mixture wasthereafter worked up as described in Example 4, the crude productcrystallized out of methylenechloride and there were recovered 5.15 g17aethinyl-5-androstene-3B,17B-diol (94percent of theory) having amelting point of 234 238C.

[ a 1 127 (Dioxan).

EXAMPLE 1] a. 17B-Acetoxy-18-methyl-5(10)-estrene-3-one (melting point145 146C) was hydrogenated with Raney nickel to 17B-acetoxy-18-methy1-5(10)-estrene- 313-01 (melting point 100 101.5C) and convertedwith methyleneiodide in the presence of zinc-copper into17B-acetoxy-18-methy1-5 1 OB-methylene-SB- estrane-3B-ol (melting point127.5 128C). After oxidation with chromic acid to form the corresponding3-ketone (melting point 140 141.5C), the 5,108- methylene ring was splitwith acid and there were recoveredl7B-acetoxy-18-methyl-4-androstene-3-one (melting point 113 114C). Inorder to form the ketal, the 3-keto group was treated withethyleneglycol in the presence of p-toluene sulfonic acid undersplitting off of water. The recovered 3,3-ethylenedioxy-17B-acetoxy-18-methyl-5-androstene (melting point 200.5 203C) wassaponified with potassium carbonate in water and methanol to form the17B-hydroxy compound (melting point 161.5 163C) which was oxidized withCrO /pyridine at room temperature to3,3-ethylenedioxy-18-methyl-5-androstene-17-one (melting point 194.5-198C). The 3,3-ethylenedioxy- 18-methyl-5-androstene-17-one was treatedwith acetic acid under heating in order to split the ketal. The therebyrecovered 18-methyl-4-androstene-3, 17-dione (melting point 141 142C)was isomerized with potassium tertiary butylate in tertiary butanol atlow temperatures and then reduced with lithiumaluminumtritertiarybutoxyhydride to 3B -hydroxy-18-methyl-5-androstene-l7-one (meltingpoint 166 168C).

b. 4g SB-Hydroxy-l8-methyl-5-androstene-17-one were introduced into asuspension of 2.15 g potassium tertiary butylate and 44 mltetrahydrofuran into which previously, for 1 hour under stirring at-15C, acetylene had been introduced. Further acetylene was thenintroduced under stirring into this mixture for 2 hours at -15C, thereaction mixture worked up as described in Example 4 and the crudeproduct crystallized out of methylenechloride. There were recovered 3.9g 18- methyl-17a-ethinyl-5-androstene-3B,17B-dio1 (90 percent of theory)having a melting point of 220 222C. (Oxidation of 3B-hydroxyl resultsthe known 18- methyl-17a-ethinyl-testosterone).

EXAMPLE 12 Acetylene was pressed into a rolling autoclave containing 20m1 tetrahydrofuran and l g potassium tertiary butylate under 2atmospheres of an over pressure of nitrogen. After an hour, theautoclave was cooled down to -l0C, the contents allowed to expand, 500

mg of racemic l8-methyl-4-estrene-3,l7-dione added, the autoclave sealedand nitrogen and acetylene again introduced. After an hour of reactiontime and the mixture was worked up as described in Example 8. There 5were recovered 400mg 17B-hydroxy-l8-methyl-l7aethinyl-4-estrene-3-one(70 percent of theory) having a melting point of 208 211C.

EXAMPLE 13 a. 6 g 18-Methyl-4-androstene-3,17-dione were dissolved in 60ml methanol, the solution reacted with 3.5 ml pyrrolidine and allowed tostand at room temperature. The separated out3-pyrrolidino-18-methyl-3,5- androstadiene-l7-one was suctioned off,washed and dried in vacuum (yield 6.3 g).

b. 6.3 g 3-Pyrrolidino-18-methyl-3,S-androstadiene- 17-one wereintroduced into a suspension, cooled to -l0C of 6.6 g potassium tertiarybutylate in 120 ml tetrahydrofuran into which acetylene had previouslybeen introduced for 1 hour. Acetylene was then introduced into theresulting mixture at 10C for an additional 3 hours. The reaction mixturewas poured into water, the tetrahydrofuran taken off in vacuum and theaqueous phase extracted with methylenechloride. By concentrating themethylenechloride phase and crystallizing the crude product out ofacetone, there were recovered 3.8 g 17B-hydroxy-18-methyl-17a-ethinyl-4-androstene-3-one having a melting point of 233 a 1,, +13.8 (Chloroform).

EXAMPLE 14 10 g 3-Methoxy-2,5(l0)-estradiene-17-one were ethinylatedover a 90 minute period at 15C as described in Example 2. The reactionmixture was dey composed with water, the tetrahydrofuran distilled offin vacuum and the separated crude product filtered off. The crudeproduct was crystallized out of methanolmethylenechloride under additionof pyridine and there were recovered 8.72 g 3-methoxy-17a-ethinyl- 2,5(10)-estradiene-17B-ol (80 percent of theory) having a melting point of192 194C. a 1,, +65.2 (Chloroform).

5 EXAMPLE 15 EXAMPLE 16 Under the conditions described in Example 4, 8gd-18-methyl-4-estrene-17-one were ethinylated. The reaction mixture wasworked up as described in Example 4 and 6,1 g d-l8-methy1-17a-ethinyl-4-estrene-17B- ol were obtained in the form of anoil. NMR: 5.38 ppm, 2.55 ppm, 0.98 ppm, IR 3608, 3300, 2925, 2870, 2830,1045.

EXAMPLE 17 Using 20 g (d-) 3-methoxy-l8-methyl-2,5( l)-estradiene-l7-one as starting material and under the conditions ofExample 1 but with the tetrahydrofuran replaced by dimethylformamide,there were recovered after working up the reaction mixture as describedin Example 1 and crystallizing out of methylenechloride 15.6 gl7B-hydroxy-l8-methyl-l7a-ethinyl-4-estrene- 3-one (75 percent oftheory) having a melting point of 234 237C.

[ a 1 33.l (chloroform).

EXAMPLE l8 Acetylene was introduced for 1 hour at 15C into a suspensionconsisting of 4,4 g Sodium tertiary amylate in 100 ml benzene-diethylether (1:1). 7,3 g 3,3 Dimethoxy-(l0)-estrene-l7-one were thenintroduced and further acetylene conducted into the resulting mixturefor one hour at C. After the reaction had ended the reaction mixture wasdecomposed by addition of dilute solution of ammonium chloride. Theorganic solution had been washed with water and after drying the organicsolvent was destilled off. The residue was dissolved in 200 ml acetoneand mixed with 12 ml concentrated hydrochloric acid. After one hour atroom tem- 1 percent);

wherein R is lower alkyl of one to three carbon atoms and A, is one ofthe following:

R being hydroxy, lower alkoxy or lower acyloxy, R

being hydrogen or methyl, X being hydrogen, lower alkoxy, lower acyloxy,morpholinol, piperidinol or pyrrolidinol, Y being hydrogen or both Ytogether constituting an hydroxy acetal or ketal protected keto groupand 2 being two hydrogen atoms or a keto group with acetylene in thepresence of an alkali alcoholate of a tertiary alcohol in a solvent inthe absence of any free tertiary alcohol.

2. Process according to claim 1 wherein R, is methyl. 3. Processaccording to claim 1 wherein said alkali alcoholate is potassiumtertiary butylate.

4. Process according to claim 1 wherein said solvent is a cyclic ether.

5. Process according to claim 4 wherein said solvent is tetrahydrofuran.

6. Process according to claim 1 which comprises conducting saidethinylation at a temperature of from +20 to 20C. i

2. Process according to claim 1 wherein R3 is methyl.
 3. Processaccording to claim 1 wherein said alkali alcoholate is potassiumtertiary butylate.
 4. Process according to claim 1 wherein said solventis a cyclic ether.
 5. Process according to claim 4 wherein said solventis tetrahydrofuran.
 6. Process according to claim 1 which comprisesconducting said ethinylation at a temperature of from +20* to -20*C.